tbuckley/cabot-search huggingface dataset:
Abstract 10554: Major Cardiac Side Effects of BTK and BCR-ABL Kinase Inhibitor Therapy in Cancer Patients: A Global WHO Database Analysis
Authors: Badri Karthikeyan, Saraswati Pokharel, Umesh C Sharma
Journal: Circulation (2022)

Introduction: Bruton’s tyrosine kinase (BTK) and BCR-ABL kinase inhibitors have transformed the treatment for hematological cancers, such as mantle cell lymphoma and chronic myelogenous leukemia. However, these therapies present unique cardiac events that remain underexplored. Hypothesis: We hypothesize that the two groups of targeted therapies commonly used to treat hematological cancers will differ in cardiac side-effect profiles. Methods: The World Health Organization database, VigiBase ®, contains over 20 million Individual Case Safety Reports and is maintained by the Uppsala Monitoring Centre. Reports for unique cardiac events associated with the use of BTK and BCR-ABL kinase inhibitors were analyzed. Reporting odds ratios (ROR), 95% confidence intervals (CI) and chi-squared tests were used to compare differences in cardiac side-effect profiles between the two groups of therapies. Results: A total of 24,385 adverse cardiac events from the use of BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib) and BCR-ABL kinase inhibitors (imatinib, dasatinib, nilotinib, bosutinib, ponatinib) have been observed based on records obtained to-date. Compared to BCR-ABL kinase inhibitors, BTK inhibitors have significantly increased reporting for atrial fibrillation (ROR: 6.995; 95% CI: 6.493-7.537; P &lt; 0.001) and ventricular tachycardia (ROR: 1.829; 95% CI: 1.342-2.493; P &lt; 0.001). However, BCR-ABL inhibitors have significantly increased reporting for myocardial infarction (ROR: 2.077; 95% CI: 1.863-2.316; P &lt; 0.001) but similar reporting for congestive cardiac failure (ROR: 0.949; 95% CI: 0.852-1.058; P = 0.343). The median onset of ventricular tachycardia from the use of BTK inhibitors is 176 days (interquartile range: 48-636 days). For BCR-ABL kinase inhibitors, the median onset of ventricular tachycardia is similar at 137 days (interquartile range: 92-396 days), P = 0.741 from nonparametric tests. Conclusion: We conclude that BTK inhibitors are associated with arrhythmic events, while BCR-ABL kinase inhibitors are associated with myocardial infarction. Both groups have similar reporting for congestive cardiac failure. Research is underway to study the mechanisms behind these novel side-effect profiles.
Abstract 10924: Assessing the Mediating Role of Three Key Factors on the Association Between Family Structure Type and Obesity in Children
Authors: Minkyoung Song, Laura L Hayman, Nathan F Dieckmann, Karen S Lyons, Carol M Musil
Journal: Circulation (2022)

Introduction: Obesity is a major risk factor for cardiometabolic disease . Research shows that children living in grandparent-headed households are more likely to have obesity compared to children living in two-parent headed households. However, little is known about modifiable risk or protective factors that influence that association. Purpose: To assess the mediator role of three key factors (families eating meals together, family resilience, and sleep duration; all reported to be associated with childhood obesity) on the association between family structure type and children’s obesity Methods: We utilized data from the 2019-2020 National Survey of Children’s Health (n=37,688 to 37,699). Path models were used to assess the mediating (indirect) effect of “frequency of families eating meals together,” “family resilience,” and “child sleeps recommended age-appropriate hours (yes or no)”, on the association between family structure type and obesity. We controlled for child’s sex, age, race/ethnicity, health insurance, number of adverse childhood experiences, and physical activity level. Results: We found that family meals was not a significant mediator between family structure type and obesity, whereas family resilience and reaching recommended age-appropriate standards for sleep were both significant mediators. Living in grandparent-headed households was associated with lower family resilience, which in turn was associated with higher odds of having obesity, after adjusting for covariates (indirect effect adjusted Odds Ratio=1.01; 95% confidence interval [1.00, 1.02]). Similarly, living in grandparent-headed households was associated with getting less sleep, which was associated with higher odds of having obesity, after adjusting for covariates (indirect effect adjusted Odds Ratio=1.04; 95% confidence interval [1.03, 1.06]). Conclusions: Although the effects were small, our findings suggest that promoting family resilience and adequate sleep could be suitable intervention targets for youth living in grandparent-headed households. Further investigations are required to validate our findings.
Abstract 10514: Compromised Cerebral Artery Integrity is Associated With Brain Tissue Injury and Cognition Deficits in Adolescents With Complex Congenital Heart Disease
Authors: Nancy A Pike, Bhaswati Roy, Cristina Cabrera-Mino, Xingfeng Shao, Nancy J Halnon, Alan B Lewis, Danny Wang, Rajesh Kumar
Journal: Circulation (2022)

Introduction: Adolescents with complex congenital heart disease (CCHD) show brain tissue injury in regions associated with cognitive deficits. Alteration in cerebral artery integrity (CAI), as measured by arterial transit time (ATT), may lead to perfusion deficits, and be a potential cause of brain injury in CCHD. To date, there are no reports of CAI in CCHD or associations between CAI, brain tissue integrity, and cognition in CCHD. Methods: 70 subjects (37 CCHD / 33 controls), 14-18 years of age, undergone surgical palliation (CCHD), and no contraindications for a magnetic resonance imaging (MRI) and healthy controls (age- and sex-matched) participated. Participants completed cognitive testing (Montreal Assessment of Cognition [MoCA] and the Wide Range Assessment of Memory and Learning [General Memory Index, GMI]) and brain MRI using 3.0 Tesla scanner. ATT values (via diffusion-weighted pseudo-continuous arterial spin labeling [pCASL] procedures), and regional brain mean diffusivity [MD] (measure of tissue integrity) were computed in whole brain. Descriptive, partial correlations, and ANCOVA analyses used (covariates, age and sex). Results: Mean MoCA [23.1 ± 4.1 vs. 28.1 ± 2.3; p &lt;.001] and GMI scores [86.8 ± 15.4 vs. 110.3 ± 14.5; p&lt;.001] show significant cognitive deficits in CCHD compared to controls. ATT was significantly increased in CCHD vs controls (mean ± SD, sec, 1.3±0.13 vs 1.22±0.13, p=0.02), respectively, indicating compromised CAI. Partial correlations between ATT, MD values, and cognition (covariates, age and sex, p&lt; 0.005) showed significant associations in various areas including the hippocampus, prefrontal cortices, cerebellum, frontal white matter, anterior and posterior cingulate, frontal cortex, temporal cortices, and midbrain. Conclusion: Adolescents with CCHD have prolonged ATTs compared to controls indicative of compromised CAI and altered cerebral perfusion. CAI is significantly associated with alterations in regional brain tissue integrity and cognitive impairment. Further evaluation is needed to test interventions to increase cerebral perfusion and to protect neural tissue.
Abstract 11028: Positive Airway Pressure Therapy for Obstructive Sleep Apnea in Heart Failure Patients With Preserved Ejection Fraction - Implications for Healthcare Resource Utilization
Authors: Atul Malhotra, Kate Cole, Anita Malik, Jean-Louis Pépin, Fatima Sert Kuniyoshi, Peter Cistulli, Adam Benjafield, Virend K Somers
Journal: Circulation (2022)

Introduction: Heart failure patients with preserved ejection fraction (HFpEF) frequently have co-morbid obstructive sleep apnea (OSA), although the impact of OSA treatment remains unclear in this patient population. We assessed the association between adherence to positive airway pressure (PAP) therapy and healthcare resource utilization in patients with OSA and HFpEF. Methods: Administrative insurance claims data linked with objective PAP therapy usage data from patients with OSA and HFpEF were used to measure the association of PAP adherence and healthcare resource utilization, defined by hospitalizations and emergency room (ER) visits. US Medicare defines PAP compliance as use for at least 4 hours/night for 70% of nights in a consecutive 30-day period over 90 days. PAP adherent patients met this criteria for all 4 90-day periods, while PAP non-adherent patients did not meet this criteria for any 90-day period over one year. Propensity score methods were used to create well matched groups with differing PAP adherence levels. Results: The study cohort consisted of 4,237 eligible patients (54.0% female, mean age 64.1 years), of whom 40% were considered adherent to PAP therapy (30% intermediate-adherent, 30% non-adherent). After propensity score matching on prior year covariates, during the year after PAP prescription, PAP adherent patients had fewer hospital visits than non-adherent patients, with a 57% reduction in hospitalizations and a 36% reduction in ER visits for PAP adherent patients (Table 1a). These results remained consistent with inverse probability weighting, and furthermore showed a significant difference in hospitalizations between intermediate-adherent and non-adherent patients, but no significant difference in ER visits (Table 1b). Conclusions: Treating OSA with PAP therapy in patients with HFpEF is associated with a reduction in hospitalizations and ER visits. Adherence to PAP therapy is required to realize these clinical benefits.
Abstract 10869: Late Pericardial Effusion After Resolution of Takotsubo Cardiomyopathy in Covid-19 Infection. A Rare but Life-threatening Complication
Authors: SaiNikhila Ghanta, Krishna Chaitanya Amerneni, Dilpat Kumar, Srikanth Vallurupalli
Journal: Circulation (2022)

Background: Various cardiac complications such as cardiomyopathy and sudden cardiac death have been associated with Coronavirus disease 2019 (COVID-19) pandemic. We present a case of late pericardial effusion after resolution of takotsubo cardiomyopathy in COVID-19. Case Report: A 46-year-old male presented with acute hypoxic respiratory failure secondary to COVID-19 pneumonia. His left ventricular ejection fraction (LVEF) was 55% at admission. Over the next two days, his condition worsened requiring mechanical ventilation and inotropic support. A repeat echocardiogram revealed severe biventricular systolic dysfunction with basal hypercontractility and a drop in LVEF to 25%. Cardiac catheterization showed clean coronaries, elevated filling pressures, and reduced cardiac index (CI:1.44L/min/m 2 ); hence cardiogenic shock secondary to viral myocarditis/takotsubo cardiomyopathy was suspected and an impella was placed. His condition improved with high-dose steroids, diuretics, and heart failure medication. He was subsequently weaned off circulatory and inotropic support and LVEF improved to 60% in four days, hence a provisional diagnosis of takotsubo cardiomyopathy was made. However, three days post-Impella removal he became tachycardic and hypotensive and a repeat echocardiogram showed moderate pericardial effusion with purulent material and Right Ventricle (RV) free wall diastolic collapse(image). He underwent emergent pericardiocentesis draining 800 ml of purulent fluid with pericardial drain placement. Pericardial fluid cultures returned negative. Thereafter, his condition significantly improved and he was discharged on hospital day 15. Conclusion: Symptomatic pericardial effusion can occur late in the clinical course even after other cardio-pulmonary symptoms have improved. This case highlights the importance of clinician awareness of the various cardiac complications in COVID-19 and their timely diagnosis and management.
Abstract 10357: Pyruvate Dehydrogenase Kinase 4 is a Novel Regulator of Endothelial Cell Mitochondrial Respiration in Diabetes-Impaired Angiogenesis: Implications for Preventing Diabetic Vascular Complications
Authors: Khalia R Primer, Joanne T Tan, Peter J Psaltis, Christina A Bursill
Journal: Circulation (2022)

Introduction: Diabetic patients have a greater risk of experiencing chronic wounds and amputation than non-diabetic patients. Ischaemia-driven angiogenesis is essential for tissue repair but is impaired in diabetes due to aberrant endothelial cell (EC) responses to ischaemia. Pyruvate dehydrogenase kinase 4 (PDK4) normally suppresses mitochondrial respiration in ischaemia by phosphorylating the pyruvate dehydrogenase complex (pPDC) to preserve EC function. However, the role of the PDK4/PDC axis in angiogenesis and the effects of diabetes are unexplored. Methods and Results: In human coronary artery endothelial cells (HCAECs), siRNA-mediated PDK4 knockdown reduced tubulogenesis (49%, P &lt;0.01) and migration (51%, P &lt;0.01), revealing an essential role for PDK4 in angiogenesis. HCAECs were exposed to 5 or 25mM glucose for 72h and hypoxia for 6h. High glucose attenuated the induction of PDK4 and pPDC in response to hypoxia. This was associated with an aberrant increase in mitochondrial respiration (20%, P &lt;0.01), measured by the Seahorse Bioanalyser system, and impaired tubulogenesis (52%, P &lt;0.001) and migration (79%, P &lt;0.0001). Lentiviral overexpression of PDK4 rescued this impairment in high glucose and hypoxia. Similarly, treatment with reconstituted high-density lipoprotein (rHDL), a known proangiogenic agent, restored the induction of PDK4 and pPDC in hypoxia and high glucose, and rescued tubulogenesis and migration. Mechanistically, rHDL increased binding of FOXO1 to the PDK4 promoter (78%, P &lt;0.05), assessed by chromatin immunoprecipitation, compared to PBS controls. In a murine model of diabetic wound healing, diabetes impaired the early induction of PDK4 and pPDC in response to wound ischaemia, and reduced wound neovessels. Topical rHDL enhanced wound PDK4 and pPDC levels over 72h post-wounding (68-165%, P &lt;0.05), and increased wound neovascularisation (62%, P &lt;0.05) and wound closure (45%, P &lt;0.001), compared to PBS controls. Conclusion: PDK4 is essential for hypoxia-driven angiogenesis. This response is impaired in diabetes and can be corrected by PDK4 overexpression and rHDL. We have identified a novel regulatory pathway for diabetes-impaired angiogenesis that can be targeted to prevent diabetic vascular complications.
Abstract 10860: Limb and Cardiovascular Event Risk in Type 1 and 2 Diabetic Patients With Peripheral Artery Disease
Authors: Daniel Sykora, Christine Firth, Marlene Girardo, Dhruv Sarma, Andrew S Tseng, Paul W Wennberg, David Liedl, Fadi Shamoun
Journal: Circulation (2022)

Introduction: Peripheral artery disease (PAD) is a risk factor for adverse limb events (LE) and cardiovascular events (CVE) that often coexists with type 1 (T1) and type 2 (T2) diabetes mellitus (DM), which differ mechanistically. There is a paucity of data on comparative risk of LE and CVE in T1DM and T2DM patients with PAD. Methods: We queried our database of 40,144 patients ≥18y old who underwent ankle brachial index (ABI) measurement from 01/1996-02/2020. We isolated patients with T1DM or T2DM and with PAD diagnosed by ABI (low [&lt;1.0] or elevated [&gt;1.4]). We retrieved demographics including hemoglobin A1c (A1c). Primary outcomes were LE (critical limb ischemia or vascular amputation) and CVE (myocardial infarction or ischemic stroke). All-cause mortality was a secondary outcome. Multivariable Cox proportional regression yielded hazard ratios (HR) with 95% confidence intervals (CI) after adjusting for age, sex, A1c, hypertension, hyperlipidemia, coronary artery disease (CAD), chronic kidney disease (CKD), and tobacco use. Results: Our study found 9,271 patients with PAD and DM (36% T1DM, 64% T2DM) with median follow-up time 34 mo (interquartile range [IQR] 85 mo). T1DM patients were younger than T2DM (mean age 67 vs 70y), with higher median A1c (7.7 [IQR 1.9] vs 6.7% [IQR 1.6]), and higher prevalence of hypertension, hyperlipidemia, CAD, and CKD. Antiplatelet and statin use did not differ. Elevated ABI was more common in T1DM (47 vs 27%). LE occurred in 23% and CVE in 12% of patients. LE risk was higher in T1DM patients than T2DM (HR 1.59[95% CI 1.45,1.74], p&lt;0.0001), but CVE and all-cause mortality did not differ significantly. Conclusions: PAD patients with T1DM had a higher LE risk than those with T2DM, even after adjustment for A1c and pertinent risk factors, but CVE risk and all-cause mortality were equivocal. These data suggest a potential role for more intensive LE risk modification in PAD patients with T1DM, but further investigation is needed to minimize limb morbidity.
Abstract 10733: Health Status Outcomes by Race in Patients Treated With Sodium-Glucose Cotransporter 2 Inhibitors: A Pooled Patient-Level Meta-Analysis of CHIEF-HF, DEFINE-HF, and PRESERVED-HF
Authors: Kashvi Gupta, John Spertus, Mary Birmingham, Kensey Gosch, James L Januzzi, Ildiko Lingvay, Javed Butler, Mikhail N Kosiborod, David E Lanfear
Journal: Circulation (2022)

Introduction Black patients with heart failure (HF) have worse health status (symptoms, function, and quality of life) compared with White patients. Reducing this disparity is a national priority. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) not only improve cardiovascular mortality and hospitalization rates in HF patients regardless of ejection fraction (EF) but also improve patients’ health status. However, because Black patients have not been well represented in global HF outcomes trials, whether the benefits of SGLT2i on health status are consistent in patients with HF regardless of race is not well understood. Methods We combined patient-level data from three US randomized, double-blinded clinical trials of SGLT2i vs. placebo, DEFINE-HF (n=263), PRESERVED-HF (n=324), and CHIEF-HF (n=448). All three trials collected the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and 12-weeks after treatment initiation. We assessed the change in the KCCQ clinical summary score (CSS, which comprises symptoms and physical limitations) by treatment arm in White and Black participants and tested the interaction of treatment by race using multivariable linear regression adjusting for trial and baseline KCCQ scores (as a restricted cubic spline). Results Among 935 participants, 236 (25%) self-identified as Black, and 469 (50.2%) were treated with an SGLT2i. Treatment-related changes in the KCCQ by race are summarized in the Table. Treatment with an SGLT2i vs. placebo resulted in 4.7-point improvement in CCS in Black patients (95% CI 0.74, 8.68; p= 0.02) and 4-point improvement in White patients (95% CI 1.69, 6.29; p=0.0007), with no treatment benefit heterogeneity by race (interaction p-value = 0.76). Conclusions The health status benefits of SGLT2i are consistent in Black and White patients. Therefore, whether improved access to SGLT2i can reduce HF-related health status disparities in Black patients should be tested.
Abstract 11029: Bioenergetic Independent Stress Signaling in the Heart Due to Mitochondrial Protein Import Stress
Authors: Arnav Rana, Xiaowen Wang, Xin Jie Chen
Journal: Circulation (2022)

Mitochondrial diseases are some of the most common genetically inherited disorders, yet the prognosis for affected patients has not drastically improved in recent years. Most therapies are supportive as the underlying biochemical derangements in these diseases are incompletely understood. Mitochondrial functions rely on the import of nuclear-encoded proteins, and it has recently been appreciated that defective import of mitochondrial proteins can result in the cytosolic accumulation of these preproteins. The accumulation of these preproteins results in cellular toxicity independently of any changes to the mitochondrial bioenergetic function, raising the possibility that mitochondrial protein import stress may be a yet uncharacterized pathway that links mitochondrial dysfunction with pathology. Here, we model this cytosolic mitochondrial precursor overaccumulation stress (mPOS) in mice through overexpression of the inner mitochondrial membrane protein Adenine Nucleotide Translocase 1 (ANT1). The goal of this study is to determine whether ANT1 can induce mPOS and tissue remodeling prior to the onset of cardiac bioenergetic defects. Using isolated cardiac mitochondria from these mice, we detected a moderate decrease in the levels of Complex I, II ,and IV. By measuring oxygen consumption in these mitochondria from 2-month-old animals, we found only a mild reduction in complex II based state 3 and 4 respirations. No change in complex I-based state 3 and 4 respirations was observed. Using RNAseq and western blot analysis, we find the robust activation of the integrated stress response (ISR). Transcriptomic data further demonstrates a strong upregulation of transcripts involved with 1-carbon metabolism, the amino acid starvation response, and proteolysis. Using echocardiographic evaluation of heart function on anesthetized mice at 6 months old, we find no significant alteration in systolic function. Together these data support the idea that mPOS may be a potent trigger of the ISR in a bioenergetics-independent manner. Whether activation of the ISR can alter cardiac function later in life is being evaluated.
Abstract 10551: Air-Ortitis
Authors: Marvyn Allen G Chan, Olamide Oyenubi, David S Gruen, Patrick Benjamin, Bisrat Teweldemedmedhin, Gerald Kristoffer E Boy, Stephen H Jesmajian
Journal: Circulation (2022)

Background: Vascular graft infections (VGI) are serious complications of open and endovascular types of surgery with 30-60% perioperative mortality and 40-60 % morbidity. High index of suspicion is necessary in patients with multiple risk factors for graft infection to ensure early detection and intervention. This is a patient who presented with occult graft infection 4 years after endovascular aortic aneurysm repair (EVAR). Case: A 79M with DM, hypertension, coronary artery disease s/p bypass surgery and angioplasty, and abdominal aortic aneurysm s/p EVAR 4 years ago, presented with mild central abdominal pain associated with nausea and loss of appetite. He denied change in bowel habits, fever, or rectal bleeding. Initial workup showed WBC 10,000/ml with left shift of 90%, together with anemia of 7g/dl. Urinalysis showed pyuria and initial blood cultures grew gram negative bacilli later revealed to be Klebsiella pneumonia. Abdominal CT then showed an aortoiliac stent in place with an air-fluid level in the native aortic aneurysm, 6.4 cm in diameter. There was immediate concern for an aorto-enteric fistula and the patient underwent exploratory laparotomy which instead revealed an infected endograft with purulent drainage to the aortic sac. The post operative period was complicated with respiratory failure, requiring intubation for a few days. Tissue culture isolated multidrug resistant Klebsiella pneumoniae necessitating a 6-week course of meropenem. After a long hospital stay, his family opted for comfort care and was discharged to a hospice facility. Conclusions: Surgical treatment of VGI is challenging and involves debridement of infected periprosthetic tissues, excision of the infected graft and secondary revascularization usually in a critically ill patient. VGI have exceedingly high mortality rates; thus, early identification, and screening of high-risk patients with infectious focus for VGI is needed.